The investigation was concerned with elucidating the mechanisms responsible for the interaction of endothelin (ET-1) with prostanoids secretion induced by angiotensin II (Ang II) or arginine vasopressin (AVP) in cerebromicrovascular endothelial cells (EC). Both Ang II or AVP induced secretion of ET-1 and prostanoids (PGD2>PGF2 and thromboxane B2). The effect of these substances was greater on ET-1 [4-146-fold over (unstimulated) controls] than on prostanoids (2-11-fold over controls) production which was inhibited by specific Ang II and AVP (AVP1)-antagonists. Indomethacin or nordihydroguaieteric acid elicited ET-1 secretion by itself and synergistically augmented the Ang II and AVP-stimulated production of ET-1 while it decreased the peptidergic induction of prostanoids. Dexamethasone-increased ET-1 secretion had little effect on AVP-induced production of ET-1 and partially decreased the AVP-stimulated Secretion of PGD2 and PGF2. The results indicate a peptidergic receptor-mediated induction of ET-1 and prostanoid secretion which can be modulated by cyclooxygenase, lipoxygenase and phospholipase A2 inhibitors. These findings may have an important pathophysiologic implication regarding the control of cerebral microcirculation under normal and pathologic conditions.